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United States Patent NEW PHENYLACETIC ESTERS AN D PRODUCTION THEREOFHenry Najer, Paris, and Pierre R. L. Giudicelli, Fontenaysous-Bois,France, assignors to Les Laboratoires Dausse (Societe Anonyme), Paris,France N Drawing. Filed July 28, 1958, Ser. No. 751,184

Claims priority, application France July 29, 1957 1 Claim. (Cl. 260-2943) It is known that spasmolytic agents are found in the class offi-diethylamino-ethyl esters of phenyl acetic acids which bear anadditional substituent on the carbon-atom to which the phenyl group islinked.

We have now found that Z-alkoxy-ethyl esters of a,-phenyl-upiperidine-acetic acid have spasmolytic, local anaesthetic andcough-relieving properties and that, having also a low toxicity, theyare highly desirable for therapeutics, particularly in the form ofwater-soluble derivatives thereof.

According to this invention we provide a new class of compoundscomprising 2-alkoxy-ethyl esters of a-phenyla-tertiary-aminoacetic acidsand water-soluble acid addition salts thereof.

We also provide a process for the production of 2- alkoxy-ethyl estersof u-phenyl-a-tertiary-amino-acetic acids, wherein 2-alkoxy-ethyl estersof a-phenyl-e-halogene-acetic acids are condensed wtih secondary aminesin the presence of agents for binding the hydrogen halide produced,preferably in an anhydrous inert organic medium.

In particular a suitable excess of the secondary amine may be employedas a binding agent for hydrogen halide. The anhydrous inert organicmedium may be provided by an aromatic hydrocarbon, particularly benzene.

The 2-alkoxy-ethyl esters of a-phenyl-a-halogeno-acetic acids,particularly a-phenyl-a-chloroacetic acid, to be employed as startingmaterial are comprised by this invention. They may be produced inaccordance with any one of the conventional esterifying methods, inparticular by reacting a-phenyl-a-halogeno-acetic acid chlorides with2-alkoxy-ethanols.

This invention is more particularly concerned with the compounds of theabove types in which the tertiaryamino group is a piperidino group andthe acid addition salts thereof, particularly the hydrochloridesthereof.

Generally the 2-alkoxy-ethyl a-phenyl-u-piperidinoacetates arecolourless liquids which can be distilled in vacuum, are soluble inethyl alcohol, ether and other usual organic solvents but are insolublein water. The hydrochlorides thereof may be obtained for example bydissolving the bases in anhydrous ether and passing dry hydrogenchloride through the ether solutions; the hydrochlorides generally arewhite, water-s0luble crystalline substances, some of which are veryhygroscopic. On the contrary the hydrobromides are not hygroscopic andthey are very soluble in water and also in ethyl alcohol. On thataccount they are generally preferred in being more convenient inhandling.

Particularly important compounds in the above class are thehydrochloride and the hydrobromide of 2-nbutoxy-ethyla-phenyl-e-piperidino-acetate. They were found to be as potent aspapaverine as a musculo-tropic spasmolytic and 5 times more localanaesthetic than procaine on rabbit cornea. In addition they shewedcoughrelieving properties 2 to 3 times more intensive than codeine.Finally the FD-SO for the hydrochloride and the hydrobromide were foundto be 155 mg./kg. and 220 mg./kg. respectively after intravenousadministration t white mice (Kaerber and Behrens method), i.e. less thanthose of procaine and codeine.

Our invention comprises cough-relieving compositions containing thehydrochloride or hydrobromide of 2-nbutoxy-ethyla-phenyl-a-piperidinoacetate or the corresponding base.

The Z-alkoxy-ethyl a-phenyl-u-chloro-acetates generally are colourlessliquids which cannot be distilled even in a high vacuum, soluble inethyl alcohol, ether and other organic solvents but insoluble in water.

The following example will illustrate this invention.

Example (a) Z-n-butoxy-ethyl u-phenyl-a-chloro-acetate.lnto a 250 ml.three-neck flask provided with a mechanical stirrer, a dropping funneland a reflux cooler, a solution of a-phenyl-a-chloro-acetic acidchloride (38 g.; 0.2 mol) in Z-n-butoxy-ethanol (30 ml.) was introduceddrop by drop in 20 minutes with continuous stirring. The mixture warmedup with evolution of hydrogen chloride. The reaction was completed byheating on a boiling waterbath for 2 hours.

The mixture was allowed to cool and 250 ml. of water was added thereto;the mixture was stirred vigorously and the separated oil extracted threetimes successively with ether (150 ml. each time). The combined etherextracts were dried over sodium sulphate and ether driven off (the lasttraces thereof on a water-bath in vacuum).

There was thus obtained 2-n-butoxy-ethyl a-phenyla-chloro-acetate (54g.; yield which was employed in crude form in the next step to bedescribed now.

(b) Z-n-butoxy-ethyl oz phenyl a piperidine acetate.--A mixture ofZ-n-butoxy-ethyl a-phenyl-a-chloroacetate (27 g.; 0.1 mol.) andpiperidine (17 g.; 0.2 mol.) in anhydrous benzene ml.) was refluxed for8 hours.

The reaction mixture was allowed to cool, piperidine hydrochloridefiltered off and washed 3 times with benzene. The filtrate to which thebenzene washing liquors were combined was distilled on a water bath toremove benzene, the oily residue triturated with water (100 ml.) thenextracted three times successively with'ether (100 ml. each time). Thecombined ether extracts were washed twice with water (70 ml. each time),dried over sodium sulphate, ether removed therefrom and the residuerectified in vacuum.

There was finally obtained Z-n-butoxy-ethyla-pheny-la-piperidino-acetate (22.1 g.; yield 69.2%) as a colourless oildistilling at 143144/0.2 mm., soluble in ethyl alcohol and ether andinsoluble in water.

(0) Hydrochloride of base (b).The base was dissolved in anhydrous etherand dry hydrogen chloride passed through the ether solution. Dried invacuum over phosphorus pentoxide, the hydrochloride which is separatedand was isolated was an amorphous, extremely hygroscopic, water-solublesubstance.

(0?) Hydrobromide of base (b).Similarly prepared by substitutinghydrogen bromide for hydrogen chloride, the hydrobromide had a meltingpoint of 99 C. (after recrystallisation from methyl-isobutyl-ketone); itwas not hygroscopic and was very soluble in water and in ethyl alcohol.

By a similar procedure we obtained:

(e) Z-methoxy-ethyl a-phenyl-a-piperidino acetate with a yield of 74%;HP. 131-132" C./0.4-0.5 mm. Hg; the hydrochloride thereof washygroscopic; the hydrobromide thereof had a M.P. of 108 C. and was verysoluble in water and in ethyl alcohol.

(f) 2-ethoxy ethyl u-phenyl-a-piperidino acetate with a yield of 67.8%;B.P. l40l4l C./0.5 mm. Hg;

Patented Dec. 6, 1960 Hg; the hydrochloride thereof was hygroscopic; thehy-.

drobromide thereof had a melting point of 90-91 C. and was very solublein water and in ethyl alcohol.

What we claim is:

A member of the class consisting of the esterof the formula thehydrochloride, and the hydrobromide of said ester;

No references cited.

